Steroids for the Prevention of Restenosis in Bare-Metal Stents — A Systematic Review and Meta-Analysis

Abstract: Introduction. Stent restenosis remains a common complication of bare-metal stent (BMS) implantation. Even in the drug-eluting stent (DES) era, there remains a significant proportion of patients who may not be eligible for DES due to inability to comply with prolonged dual antiplatelet therapy. We reviewed the validity of empirical evidence that periprocedural treatment with steroids at the time of insertion of a BMS may delay restenosis and provide benefit through reductions in adverse clinical events. Methods. We searched the PubMed, EMBASE and Cochrane Central Register of Controlled Trials databases for randomized controlled trials conducted between 1990 and 2011 that assessed the impact of systemic steroid administration within 72 hours to 7 days of angioplasty alone and BMS placement. The comparator included standard medical therapy and/or placebo. Outcomes assessed were: (1) rates of restenosis at the end of at least 6 months of follow-up; (2) rates of target vessel revascularization; and (3) risk of all-cause mortality. The methodological quality of the studies was assessed, as was publication bias. Relative risk of restenosis, revascularization, and rates of in-hospital mortality for treatment and control groups were compared using a random effects model (Mantel-Haenszel). Results. We identified 5 studies that met inclusion criteria. No significant reduction in restenosis rates was observed after angioplasty alone with steroids. However, with BMS, significant reductions in restenosis rates (relative risk [RR], 0.60; 95% confidence interval [CI], 0.37-0.97; P=.04), and target vessel revascularization rates (RR, 0.56; 95% CI, 0.34-0.92; P=.02) were observed in the steroid-treated group. A 28% mortality reduction was observed with steroid treatment with BMS placement, but was not statistically significant. Conclusion. Periprocedural steroid administration during BMS implantation may reduce rates of restenosis and target vessel revascularization, without adverse clinical effects attributable to steroid use.

J INVASIVE CARDIOL 2012;24:98–103

Key words: steroids, stents, restenosis, inflammation

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In the pre-stent era, periprocedural steroids were attempted to reduce restenosis rates, fuelled mainly by preclinical studies.1 However, the hypothesis of periprocedural steroids to prevent restenosis rates in human studies did not prove effective.2 Bare-metal stents (BMS) came into wide usage and provided improvement in restenosis rates to some extent. Percutaneous coronary intervention (PCI) of stenosed coronary arteries using BMS is associated with restenosis in 10%-50% of patients.3,4 Restenosis after stent implantation is caused by neointimal proliferation through stent struts.5 Experimental studies indicate a marked activation of inflammatory cells at the site of stent struts, which likely plays a key role in the process of neointimal proliferation and restenosis.2 Corticosteroids may inhibit neointimal hyperplasia because of their potent anti-inflammatory properties and have been reported to attenuate neointimal formation in experimental models.6 Experimental data from atherosclerotic animal models support the efficacy of oral prednisone treatment in reducing restenosis after BMS implantation.7

Nonetheless, some studies of steroid use after angioplasty in humans failed to demonstrate reductions in angiographic restenosis.8-11 The reasons for this failure are not clear, but may be related to suboptimal dosage and duration of steroid treatment.12 Drug-eluting stents (DES) effectively reduce restenosis rates, but their use has been linked to increased late thrombosis rates and the need for prolonged dual antiplatelet therapy (DAPT). Concern about effectiveness of prolonged DAPT has been raised with the emergence of data concerning clopidogrel resistance13 and interactions.14 Studies using high immunosuppressive doses of prednisone7 yielded positive results compared to placebo after single BMS implantation in selected patients with evidence of high CRP levels,15 and in observational studies performed in patients with multivessel disease.16 High-intensity steroid treatment also showed good clinical and angiographic effects in treatment of bifurcation lesions.17

A recent randomized, controlled study comparing the clinical outcomes obtained in a control group of patients treated with BMS versus two other study groups — BMS plus oral prednisone or DES ­— showed that both BMS plus prednisone treatment and DES implantation resulted in better event-free survival at 1 year than BMS alone.18 Despite these findings, use of high-intensity steroid treatment with BMS placement has not been adopted clinically.

The aim of this meta-analysis was to systematically review the literature for controlled randomized studies to evaluate the role of corticosteroids in reducing the rate of restenosis in patients after balloon angioplasty alone and after successful BMS implantation.

Methods

Search strategy. We searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trials for trials that randomized study participants to steroids prior to angioplasty with or without stent placement versus placebo/standard therapy, between 1990 and 2011. The following medical subject heading (MeSH) terms were included for MEDLINE search and adapted for other databases as needed: ‘steroids and angioplasty,’ ‘steroids and PTCA,’ ‘bare-metal stent and steroids,’ ‘steroid and prevention of restenosis in bare-metal stents,’ and ‘prevention of restenosis of bare-metal stents.’ In addition to searching these databases, the reference lists of all identified studies, meta-analyses, and reviews were reviewed manually. No language restriction was imposed on the search.

Inclusion and exclusion criteria. We included trials that studied adult patients (18+ years) who had a recent angioplasty or placement of BMS(s) and received periprocedural corticosteroids (within 72 hours before stent implantation up to 7 days after stent placement). Eligible trials had to be randomized clinical trials comparing restenosis rates with and without periprocedural steroids having a minimum follow-up duration of 6 months. Animal studies as well as pathological analyses were excluded, as were subgroup analyses from trials.

Data collection and processing. Two authors (SC, PS) reviewed the trials to ensure that they met inclusion criteria and abstracted the data. Disagreements were resolved by consensus (approximately 10% of the time). We performed objective assessment of the trials using the methods specified in the Cochrane Handbook of Systematic Reviews,19 assessing each study based on randomization, concealment, blinding, intention to treat, baseline comparisons, concomitant interventions, and completeness of follow-up.

Outcomes assessment. The primary endpoint of interest was rate of restenosis at the end of at least 6 months of follow-up. Secondary outcomes of interest were all-cause mortality and rates of target vessel revascularization. The maximum duration of follow-up assessed was 1.2 years. Statistical analysis. Meta-analysis was performed as per the recommendation of the Cochrane collaboration19 and in line with the PRISMA statement.20 Pooled treatment effects were estimated by developing risk ratios, using the Mantel-Haenszel random-effects model. Heterogeneity was assessed using chi-square tests and the I2 statistic; we defined I2 <50% to be low heterogeneity. We assessed relative risk for data with heterogeneity, and as per Cochrane metrics, publication bias was estimated using funnel plots and the regression test of Egger.21 For statistical analysis, we used Review Manager Version 5.1 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008).

Results

Our MEDLINE search returned 15 studies. After elimination of duplicate results, the EMBASE and Cochrane registries did not return any additional studies. Through a review of titles and abstracts, 10 studies were rejected for relevance. The remaining 5 studies met all criteria and were included in this analysis (Figure 1).

Study characteristics. The two included studies for steroids in angioplasty alone were randomized clinical trial with a pooled sample size of 652 patients. The three included studies for steroids after stent placement were randomized clinical trials, reporting information on 473 patients. All trials met PRISMA criteria for high quality. The trials were fairly homogenous with respect to inclusion and exclusion criteria, with a few key differences (Table 1). Timing of steroid administration varied from 48 hours before stent implantation to immediately after stent implantation. All participants received standard medical therapy as adjunct after stent implantation — the only difference in treatment modality being the intervention of steroids in the experimental arm. One study only randomized patients with elevated CRP levels15 after stent implantation; two excluded diabetic patients15,22 (Table 1).

Primary outcome. Restenosis rates were not affected by steroid use as an adjunct to angioplasty alone (RR, 1.02; 95% CI, 0.84-1.23; P=.85; Figure 6). Periprocedural steroid therapy with BMS insertion significantly reduced the risk of restenosis rates on follow-up (RR, 0.60; 95% CI, 0.37-0.97; P=.04) when compared with controls. However, heterogeneity was moderate for this endpoint (I2 = 54%; P=.12). Publication bias was found to be low (Figure 5).

Secondary outcomes. Event rates were low for both treatment arms. A non-significant trend in reduction in mortality was observed among those assigned to receive periprocedural steroids (Figure 3). TVR was reduced significantly with steroid treatment (RR, 0.56; 95% CI, 0.34-0.92; P=.02; Figure 4), but heterogeneity for this endpoint tended to significance (I2 = 42%; P=.18). Publication bias for mortality and TVR were low.

Discussion

Our review suggests use of oral high-potency corticosteroids may provide a restenosis benefit in patients treated with BMS. This observation differs from a pooled analysis of steroid use as an adjunct to balloon angioplasty without stent use, which found that restenosis rates were not affected by steroid use (RR, 1.02; 95% CI, 0.84-1.23; P=.85; Figure 6). It has been postulated that approximately 70% of the restenosis was due to elastic recoil and negative remodelling. On the other hand, the mechanism of restenosis in BMSs is due entirely to intimal hyperplasia, as a result of the cellular processes activated in response to the injury of barotrauma. This makes a logical case for steroid use in an effort to attenuate the hyperplastic response after BMS placement. A likely mechanism whereby steroids may prevent restenosis after BMS placement would be through inhibitory effects on inflammatory mediators and receptors, platelet function, smooth muscle proliferation, and collagen formation.22,23 Maximal effects would require high doses of steroids, but this may result in limiting side effects. The authors of the CEREA-DES study noted water retention, facial edema and transient hyperglycemia in a small proportion (5%-15%) of study patients receiving high-dose corticosteroids. However, in the IMPRESS study, oral steroids for 45 days after BMS ,with high dosages received for the first 10 days, were remarkably free of side effects (very few instances of gastric pain, transient glucose intolerance, and hypertension were noted). These studies did not report evidence of hypothalamic-pituitary-adrenal axis suppression24 or significant psychiatric side effects.25 However, steroids have multiple side effects including diabetes and importantly that could affect the lipid profile indirectly by increasing low-density lipoprotein. Although in the included studies there were no reports of significant worsening of glycemic or lipid control, with greater duration of therapy and longer follow-up, eventually we may need to increase usage of antidiabetic and lipid-lowering medications.

Without undermining the importance of seeking a solution to the need for prolonged DAP therapy in patients who receive DES, corticosteroids seem to offer an attractive enhancement to the efficacy of BMS.

Limitations

This analysis was limited to the five published studies pertaining to patients treated in randomized clinical trials receiving moderate to high doses of oral corticosteroids to assess impact on angiographic restenosis and adverse clinical events. The power of the analysis is limited accordingly. In addition, the cohort of patients under study in one publication was restricted to patients with elevated CRP levels.15 Thus, the applicability of the observations to a less selected population is uncertain.Long-term side effects of steroid use with high doses were not studied, like for osteoporosis which could lead to fracture hip and could lead to increase the mortality indirectly — though the risk is probably attenuated with short-term pulse use of steroids as in most of the included studies. Heterogeneity in the results indicates the need for larger randomized studies. Also, longer-term outcomes data remain awaited.

Conclusion

Our review found that oral steroids administered within 72 hours of BMS implantation and continued after stent placement significantly reduced restenosis at 6-12 months. TVR was also reduced importantly, and steroid use was associated with a nonsignificant 28% reduction in all-cause mortality.